Bimetallic nanoplatform for synergistic sonodynamic-calcium overload therapy utilizing self-supplied hydrogen peroxide and relieved hypoxia.

Sonodynamic therapy (SDT) has emerged as a potential alternative to traditional cancer treatments as it offers deep cellular penetration and reduced invasivity. Sonosensitizers generate reactive oxygen species (ROS) under ultrasound activation, focusing the ultrasound energy on malignant sites located deep in tissues and causing cell apoptosis and necrosis. However, due to tumor hypoxia and the limited levels of intracellular endogenous hydrogen peroxide (HO is a fundamental species for supplying oxygen catalase activity), SDT efficacy is still insufficient. In this study, a bimetallic and multifunctional system (FeO-TAPP@PVP-CaO) was prepared by using ferrosoferric oxide (FeO) as a carrier loaded with 5,10,15,20-tetrakis(4-aminophenyl), porphyrin (TAPP), that was then coated with polyvinyl pyrrolidone (PVP) and calcium peroxide (CaO). The CaO layer elevated the levels of HO and Ca in the tumor microenvironment when exposed to intracellular acidity, providing essential elements for oxygen generation. Intracellular hypoxia was alleviated the catalase-like activity of FeO inducing calcium overload. Under ultrasonic irradiation, SDT generated toxic reactive oxygen species (ROS, singlet oxygen) and activated calcium influx through acoustic cavitation. Meanwhile, calcium overload therapy efficiently induced cell apoptosis at the moment of uncontrollable cellular accumulation of Ca. In addition, we modified the PVP on the surface to make it more stable. This study presents a bimetallic nanoplatform that can efficiently induce cancer cell death by synergistic sonodynamic-calcium overload therapy modulation of O/ROS/Ca species, indicating its potential for multi-modality cancer therapy.